Although the major fuels used during exercise are carbohydrates and fats the contribution made by protein is important. The breakdown of protein leads to amino acids that can replenish the citric acid cycle intermediates that are lost by oxidative processes when the carbohydrate stores are low. The long term objectives of this research are to determine how the rate of muscle protein degradation is affected by exercise, the mechanism of exercise-induced protein degradation, and the physiological regulation of protein degradation. The effect of exercise on protein degradation is controversial because a through study has not been performed. The differing results of previous studies can be explained by the central hypothesis in this proposal. This hypothesis is that the effect of exercise on muscle protein degradation depends on the type of muscle protein studied, the type of exercise performed, and the time the measurements were made in relation to the time the exercise was performed. In the proposed studies the rate of total and myofibrillar protein degradation will be determined by measuring the release of tyrosine and 3-methylhistidine, respectively, from the perfused rat hindlimb. These measurements will be made before, during, and after exercise. The contribution of muscle damage to the effect of exercise on muscle protein degradation will be determined by subjecting some of the animals to muscle damaging eccentric exercise. The mechanism off exercise-induced protein degradation will be probed by measuring the initial events in the degradation of muscle proteins, determining how lysosomes are involved, and determining how the activity of muscle proteinases and their inhibitors are altered during and after exercise. The effect of physiological regulators on the exercise-induced changes in the rate of protein degradation will be studied by changing the concentrations of these regulators either directly or indirectly by the use of inhibitors. The regulators studied will include the energy charge, H+, Ca2+, insulin, leucine, and PGE2. The results of these proposed studies will not only clear up the controversy concerning the effect of exercise on protein metabolism, but will also yield important basic information necessary for an understanding of the mechanism and regulation of protein degradation in general. This information could find application in the treatment of muscle wasting conditions such as fever, sepsis, traumatic injuries, and cancer.